Cancer is a progressive disease in which a tumor cell develops qualitatively new transformation related phenotypes or a further elaboration of existing transformation associated properties. Defining the molecular determinants of progression should lead to improved cancer diagnosis and strategies for therapy. Subtraction hybridization identified a novel gene associated with induction of transformation progression in virus and oncogene transformed rat embryo cells, progression elevated gene-3 (rPEG-3). rPEG-3 expression correlates directly with the progression state in rodent cells. Ectopic expression of rPEG-3 in transformed rodent cells or human cancer cells elicits genomic instability, angiogenesis and an aggressive oncogenic phenotype, whereas antisense inhibition of rPEG-3 expression eliminates many of these traits in rodent tumors, rPEG-3 has sequence homology to the growth arrest and DNA damage inducible hamster gene gadd34, which displays potent growth suppressing and apoptosis promoting properties. Mutation of the human gadd34 gene converts this gene into a huPEG-like gene, with cancer progression promoting properties, including direct augmentation of the transformed phenotype and increased VEGF expression. Our working hypothesis is that rPEG-3 and huPEG-like gene expression is a downstream event in oncogenic transformation and progression and activation of PEG-3 may directly alter the expression of genes involved in cancer progression, including genes associated with tumorigenesis, metastasis and angiogenesis. Studies will focus on cloning a HuPEG-3 gene (or its equivalent) and evaluating the effect of transient and stable expression of sense and antisense rPEG-3 and huPEG-like constructs in transformed cells on transformation progression in vitro and in vivo. Experiments will focus on defining the mechanism of action of rPEG-3 and huPEG-like gene expression in human cancer development and progression. Emphasis will be placed on the ability of these genes to induce genomic instability and to induce angiogenesis in cancer cells. These studies will provide important insights into a novel progression gene with potential relevance to human cancer development and evolution. The huPEG-3-like gene may serve as a target for selectively intervening in the progression process, thereby preventing cancer aggressiveness and metastasis.